J . Am. Chem. SOC.1991, 113, 1288-1294
1288
solvent and excess substrate were evaporated in vacuo, and the products were separated by thin-layer chromatography on silica gel with pentane eluent. The products obtained in the presence of EtMe2SiH (93% conversion of starting material) were Ad2SiH2 (22%), PhSiMe2SiAd2H (27%), (EtMe2Si), (9%), and HSiAd2SiEtMe2(1%). In the presence of 2,3-dimethylbutadiene, the products were Ad2SiH2 (24%), PhSiMe2SiAd2H (23%), and PhSiMe2SiAd2CH2CHMeCMe=CH2 (6%). PhSiMe2SiAd2H:'H NMR (C6D6)8 0.57 (s, 6 H, SiMe), 1.71 (m, 12 H, Ad), 1.79 (m, 6 H, Ad), 1.96 (m, 12 H, Ad), 3.48 (s, 1 H, SiH), 7.22 (m, 3 H, Ph), 7.62 (m, 2 H, Ph). (EtSiMe2)2:'H NMR (C6D6) 6 0.01 (s, 12 H, SiMe), 0.58 (q, 4 H, J = 7.8 Hz, Et CHI), 0.99 (t, 6 H, J = 7.8 Hz, Et CH,). PhSiMe2SiAd2CH2CHMeCMe=CH2: IH NMR (C6D6)6 0.20-0.45 (m. 8 H , SiCH2, SiMe), 0.9 (m, 3 H, Me), 1.35 (s, 3 H, Me), 1.79 (m, 12 H, Ad), 1.85 (m, 6 H, Ad), 1.95 (s, 12 H, Ad), 5.00 (m,2 H, =CH2),
7.2-7.5 (m, 5 H, Ph). Photolysis and Thermolysisof 1,l-Diadamantylsiliranes.Photolysis. The reaction mixture was loaded into a quartz sample tube (6 mm (0.d.) X 4 mm (i.d.) X 20 cm) connected via a stainless steel sleeve to a Teflon high-vacuum stopcock. After being degassed to 0.02 Torr by freezepump-thaw cycles on a vacuum line, the reaction mixture was irradiated with an array of low-pressure mercury lamps in a Rayonet photochemical reactor. After irradiation, the reaction mixture was unloaded in a drybox, and solvent and excess volatile substrates were evaporated under reduced pressure. Thermolysis. The reaction mixture was placed in a Pyrex tube ( 6 mm (0.d.) X 4 mm (i.d.) X 20 cm) with a preformed constriction, attached via a stainless steel adapter to a Teflon high-vacuum stopcock. After being degassed on a vacuum line by freeze-pump-thaw cycles to 0.02
Torr, the sample tube was sealed and then placed in a preheated oil bath. After thermolysis, the sealed tube was opened in a drybox, and solvent and excess volatile substrates were evaporated in vacuo. The results from both photolysis and pyrolysis experiments, including quantities of reagents, reaction times and temperatures, conversions, product yields, and the isomeric composition of recovered starting and product siliranes are given in Schemes 111-V and for competition experiments in Scheme VII.
Acknowledgment. W e are grateful to the United States National Science Foundation for encouragement and support of this research under Grant No. CHE-88-02677. Professor Maitland Jones, Jr., provided the original stimulus for this project. W e thank Professor Robert T. Conlin for helpful discussions and exchange of unpublished results. We are grateful to Dr. Andrew Tyler, Ms. Janet Braddock Wilking, and Mr. Dallas New for recording mass spectra, which were obtained a t the Washington University Mass Spectrometry Resource, which is supported by National Institutes of Health Grant No. RR00954. T h e Washington University X-ray Crystallography Facility has received support from the NSF Chemical Instrumentation Program, Grant No. CHE-88-11456. Supplementary Material Available: Crystal structure drawing, diagram of unit cell, structure determination summary and tables of atomic coordinates, bond lengths, bond angles, anisotropic displacement coefficients, and H atom coordinates ( 1 1 pages); observed and calculated structure factors (18 pages). Ordering information is given on any current masthead page.
Predominant *O Exchange Accompanying Base Hydrolysis of a Tertiary Toluamide: N-Ethyl-N-( trifluoroethy1)toluamide. Assessment of the Factors That Influence Partitioning of Anionic Tetrahedral Intermediates H. Slebocka-Tilk, A. J. Bennet, Heather J. Hogg,+and R. S . Brown* Contributionfrom the Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2. Received May 31, 1990
Abstract: The hydrolysis of N-ethyl-N-(trifluoroethyl)toluamide(Ill) in basic media at 100 "C ( p = 1.0 (KCI)) is reported. '*O exchange in 111 recovered from the hydrolytic medium is observed: kex/khyd = 33.4 i 1.6 and is independent of [OH-]. The low basicity of the amine in 111 (pK,(H2+N(Et)CH2CF,) = 6.3) leads to 2300-3500-fold more exchange in 111 relative to N,N-dimethyltoluamide ( I ) or N-toluoylpyrrolidine (11). These findings indicate that amine leaving ability controls whether a tcrtiary amide will exhibit I8O exchange and that restriction of conformational mobility in the manner required by the Deslongchamps' stereoelectronic theory is of little importance in the exchange process. Solvent deuterium kinetic isotope data for I l l indicate that ( k e x ) H I= D 0.90 A 0.08 and (khyd)H,D = 1.05 A 0.04. These respective solvent kinetic isotope effects (SKIE) refer csscntially to isolated kinetic processes k, (the attack of OH- to form To-) and k2 (the breakdown of the anionic intermediate to product). The small observed SKIE on exchange and hydrolysis is analyzed in terms of the fractionation factors for species involved in the transition states leading to the anionic tetrahedral intermediate To- and away from it, respectively. The mechanism consistent for the SKIE on khyd is suggested to involve rate-limiting breakdown of one or both of two anionic forms having a protonated N, an anionic zwitterion Tzw- or a neutral zwitterion with an encounter complex associated OH-. On the basis of SKIE, I8O exchange, and hydrolysis data for a series of tertiary toluamides having an amine portion varying in basicity by 14 pK units, a unified mechanism for base-promoted hydrolysis is presented.
-
Introduction Carbonyl I8Oexchange has been extensively used to determine the partitioning of anionic intermediates produced during the hydrolysis of amides in base.'" The current scheme that accounts for the observed l8O exchange is given in eq 1 and involves one or more reversibly formed intermediates ( e g , To-) in which the I6O and I8O atoms are in protonic equilibrium (or near equilibrium). Undergraduate research participant. 0002-7863/91/ 15 13-1288$02.50/0
The order of I8O exchange for previously investigated benz> secondary >> tertiary, amides'V2 and t o l ~ a m i d e sis~ .primary ~ (1) (a) Bender, M. L. J . Am. Chem. SOC.1951,73. 1626. (b) Bender, M. L.; Ginger, R. D.; Kemp, K. C. Ibid. 1954, 76, 5350. (c) Bender, M . L.; Ginger, R. D. Ibid. 1955, 77, 348. (d) Bender, M. L.; Ginger, R. D.; Unik, J. P.Ibid.1958.80, 1044. (e) Bender, M. L.; Thomas, R. J . Ibid.1961,83, 4183. (2) (a) Bunton, C. A.; Nayak, B.; O'Connor, C. J . J . Org. Chem. 1968, 33, 572. (b) Bunton, C. A.; Lewis, T. A.; Llewellyn, D. R. Chem. Ind. (London)1954, 1 1 54. (c) Bunton, C. A.; Spatcher. D. N. J . Chem. Sor. 1971, 36, 3870.
0 1991 American Chemical Society
Base Hydrolysis of a Tertiary Amide
J . Am. Chem. SOC.,Vol. 113, No. 4, 1991
1289
Experimental Section
TO-
H ?I;.[
/
/
0-
Tmand we have recently shown this to be attributable to the relative amine leaving ability (LA) from the anionic tetrahedral intermediate.7 From DzOsolvent kinetic isotope effect studies on the kex/khydratios (defined as kex/khyd= k - , / 2 k 2 ) for two tertiary toluamides (N,N-dimethyltoluamide (I) and N-toluoylpyrrolidine (II)), we have proposed that the breakdown of To- to products involves the rapid formation of an anionic zwitterion TZw-followed by a slower C-N cleavages7
I: R i = R2 = CH3 11: R1 = Rz = (CH& 111: Ri = CHzCF3; R2 = CH2CH3 Iv:Ri I CHzCH3; R2 = H
Two definitive conclusions arise from our previous s t ~ d y .First, ~ since amine L A determines whether '*Oexchange will be observed during OH--promoted amide hydrolysis, it is unnecessary to postulate that lack of exchange in tertiary benzamides or toluamides is attributable either to stereoelectronic effects4 or to inability to achieve protonic equilibration of the I6O and '*O atomsSza Second, since the kex/khydratios for I and 11 are 0.01-0.01 5 and 0.013-0.02, respectively, ( T = 100 OC, p = 1 .O) and are independent of [OH-], the rate-limiting step for both hydrolysis and exchange is k , . Thus, for the tertiary benz- and toluamides heretofore investigated it is difficult to obtain good mechanistic information about the product-forming transition state ( k , in eq 1). This is because the low observed I8O exchange is subject to unavoidably large experimental uncertainties that complicate the comparison of kex/khydin H 2 0 and D@, which have bearing on the mechanistic evaluation. In order to address the above problem, we have sought a tertiary toluamide that possesses an amine with a diminished LA, which would raise the k2 barrier above that of k - , . Herein we report our findings with the N-ethyl-N-trifluoroethylderivative 111, which shows a surprisingly large kex/khydratio of 33.4 f 1.6 in N a O H ( T = 100 "C). As well, we present kinetic solvent isotope exchange and hydrolysis data for 111 and IV along with activation parameters for the hydrolysis of 1-111 and some other tertiary toluamides. These data allow a detailed mechanistic analysis to be made for a series of toluamides in which the rate-limiting steps vary from OH- attack ( k , for I and 11) to breakdown of the anionic intermediates ( k , for 111). (3) DeWolfe, R. H.; Newcomb, R. C. J . Urg. Chem. 1971, 36, 3870. (4) (a) Deslongchamps, P.; Cheriyan, U. 0.;Guida, A,; Taillefer, R. J. Nouu. J . Chim. 1977, I , 235. (b) Deslongchamps, P.; Gerval, P.; Cheriyan, U. 0.;Guida, A.; Taillefer, R. J. Nouu. J . Chim. 1978, 2, 631. (c) Deslongchamps, P.; Bartlett, R.; Taillefer, R. J . Can. J . Chem. 1980, 58, 2167. (5) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon: Oxford, 1983. (b) For discussion of this point, see ref 5a, pp 108-1 18. ( 6 ) (a) Slebocka-Tilk,H.;
Brown, R. S. J . Og. Chem. 1988,53, 1153. (b) Slebocka-Tilk, H.; Brown, R. S. fbid. 1987, 52, 805. (7) Slebocka-Tilk,H.; Bennet, A. J.; Brown, R. S.;Guthrie, J. P.; Jodhan, A. J . Am. Chem. Soc. 1990, in press.
(a) Materials. N-Ethyltoluamide (IV) was prepared as previously de~cribed,~ as were Pa and 11.' N-Ethyl-N-(trifluoroethy1)amine was prepared by a modification of a reported procedure8 as follows. To an ice-cooled solution containing 30.26 mL of trifluoroacetic anhydride in 175 mL of dry ether was added dropwise a solution of 34 mL of ethylamine in 75 mL of ether. After the addition was complete, the mixture was stirred for an additional 15 min and then filtered. The filtrate was concentrated and the residue distilled (water aspirator, 55 "C) to give 17.2 g of N-ethyltrifluoroacetamide (57%). Reduction was accomplished by addition of a solution of 10 g (71 mmol) of N-ethyltrifluoroacetamide in 500 mL of dry ether to a stirred mixture of 4. I g of LiAIH, in 150 mL of ether at such a rate as to induce gentle reflux. The resulting mixture was heated at reflux for 72 h after which it was cooled and quenched by the dropwise addition of IO mL of HzO, followed by IO mL of 15% aqueous NaOH and then a further 30 mL of HzO. The resulting mixture was stirred for 20 min and then filtered. The solid was washed with 3 X 20 mL of ether, the combined filtrate and ethereal washings were then extracted with 3 X 40 mL of H20,and the solid was dried (MgSO,). After filtration, the ether solution was flushed with HCI gas until no further precipitation was observed and then filtered to yield 8.7 g (75%) of the HCI salt of Nethyl-N-(trifluoroethy1)amine: 'H NMR (D20) 6 1.34 (t, 3 H, J = 7 Hz), 3.29 (q, 2 H, J = 7 Hz), 3.98 (q, 2 H, J = 9 Hz); IR (KBr disk) 3400-2600 (br), 2557,2441,2394, 1598, 1480, 1424, 1353, 1270, 1207, 1186, 1 1 IO, 1047 cm-'; exact mass for C4H8NF3,calcd 127.0609, found 127.0613. N-Ethyl-N-(trifluoroethy1)toluamide(111) was prepared by the addition of 1.72 g (1 1 mmol) ofp-toluoyl chloride to a solution consisting of 2.0 g (12 mmol) of the above amine hydrochloride salt, 2.0 mL of HzO, and 5 mL of triethylamine. The mixture was allowed to stand for 30 min after which it was extracted with CH2CIz (2 X 20 mL). The combined organic extracts were washed with IO mL of 0.01 N HCI, then dried (MgSO,), and stripped of solvent. The residue was distilled at 100 O C / O . 5 Torr to yield 2.3 g (82%) of the desired amide: 'H NMR (50 oC,CDCI,)61.15(t,3H,J=6Hz),2.39(s,3H),3.53(q,2H,J= 6 Hz), 4.10 (br q, 2 H, J = 7.2 Hz), 7.26 (4 H, AA'BB'); IR (film) 1659 cm-I; exact mass for C~zH~4NOF,; calcd 245.1027, found 245.1026. Anal. Calcd for C12H14NOF3: C, 58.77; H, 5.75; N, 5.71. Found: C, 59.06; H, 5.80; N, 5.61. The 50% I80-labeled amide 111 was prepared exactly ab above with the exception that -50% '80-labeled toluoyl chloride7 was used. (b) Kinetics. (i) The rates of hydrolysis of 111 and IV studied were determined by 'H NMR analyses (Bruker WH-400 spectrometer) with methodologies previously de~cribed.~ The low solubility of 111 in H 2 0 or D20 necessitated a slightly modified procedure. A series of I O 30-mL samples of NaOH (- 1.0 or 0.1 N, p = 1.0 (KCI)) containing 4% (by volume) of DME for solubility and 3 mg (0.4 mmol) of 111 were placed in 30" Teflon FEP centrifuge tubes, which were sealed with Nalgene leak-proof caps having Teflon liners. Solutions of base in either HzO or D20 were prepared under COz-freeconditions in an Ar-filled drybox and stored under Ar. All subsequent operations with these solutions were performed in the Ar-filled drybox. OD-/DzO solutions were prepared by dissolving the appropriate amount of Na metal in D20. Base concentrations were determined by titration with standardized 1.0 or 0.1 N HCI, phenolphthalein indicator. The charged, sealed, FEP tubes were then thermostatcd at 100 OC (boiling H 2 0vapor) and removed at various times. The tube corresponding to time zero ( t o ) was removed after a 15-min equilibration period. After removal of the tubes, they were cooled and the contents transferred to a 50-mL separatory funnel containing 1 .O m L of CDZCIzNMR solvent. The contents were shaken and the phases allowed to separate after which the CD2CI2layer was carefully pipetted out, dried (MgSO,), and subjected to 'H NMR analysis. The residual H in CDZCIzprovided an internal reference that was integrated and compared with the intensity of the signal at 6 7.25 attributable to the aromatic protons of the recovered unreacted amide. A control second extraction experiment was conducted with use of I .O mL of fresh CD2CI2 to rcextract the solution. No amide was observed in the second CD2C12 extract, which confirmed that all the amide was removed by the first 1 .O mL of CD2CIz. The hydrolysis kinetics were unable to be monitored by U V techniques since thc absorbance vs time plots showed marked deviation from firstorder behavior. This was found to be due to a subsequent reaction of the N-cthyl-N-(1rifluoroethy1)amine produced from hydrolysis of the amide. Thus, an aqueous solution containing base and IOF4 M each of the au(8) Sakamoto, S.; Tsuchiya, T.; Tanaka, A.; Umezawa, S.; Hamada, S.; Umezawa, H. J . Antibiot. 1984, 37, 1628.
Slebocka- Tilk et al.
1290 J . Am. Chem. SOC.,Vol, I 1 3, No. 4, 1991
Table I. Hydrolysis and Exchange Rate Constants for Toluamides I11 and IV in Basic Media" amide lOL-1 (MI k h y d (S-') LOL-1 (MI k,, (s-') ker/khyd I l l (H,O) I .08 (3.38 f 0.09) X 1.08 ( I .09 0.02) x 10-3 32.2 f 1.6 0.205 (6.26 f 0.1 1) X 10" 0.095 ( I .oo i 0.01) x I 0-4 34.5 f 1.0 (3.06 f 0.03) X 1.03 (1.09 f 0.03) X 35.6 f 1.4 I l l (D2O) I .03 IV ( H 2 0 ) b 0.926 (1.07 f 0.02) X IO4 0.933 (5.24 f 0.15) X 0.49 f 0.03c 0.13 ( I .46 f 0.02) X I 0-5 0.086 (4.85 f 0.10) X IOd 0.50 f 0.02c IV (D,O) 1.03 (1.10 i 0.02) x 10-4 1.06 (5.87 f 0.27) X 0.53 f 0.04c a T = 100 "C, p = 1.0 (KCI). *Data from ref 7. CWhere[OL-] is different for a given hydrolysis and exchange experiment, pseudo-first-order rate constants were converted to second-order rate constants for determining kex/khvdratios. ~
thentic toluic acid and amine products was shown to exhibit a changing UV spectrum when heated at 70 'C. The final U V spectrum of this solution matched an infinity spectrum for the hydrolysis of M 111 under the same conditions at 70 OC. The hydrolysis rate constants (khyd)were evaluated from the slopes of the plots of In (f(amide)/f(reference) vs time plots, where I refers to the integrated intensity of the residual amide aromatic and reference CDHCI2 peaks. Each reaction was followed to 2 or more half-lives and the quoted error limits are those of the standard deviations obtained from linear least-squares treatment of the In f vs time plots. (ii) The rates of exchange were assessed with methodologies and mass spectrometric instrumentation previously de~cribed.~,'Exchange rate constants (ke,) were evaluated from the slopes of the plots of In [fM++>/(fM+ + fM++2)] vs time where I represents the intensity of the parent and parent + 2 mass ions. Eight points up to at least 2 half-lives were taken for each plot, and the errors in the quoted k,, values were determined as the standard deviation of the linear regression lines.
~~~~
With the above reservations in mind, a likely choice for comparison with I or I1 would require a secondary amine with steric requirements similar to HN(CH,), or pyrrolidine, but a vastly lower basicity. Thus, HN(CH2CH3)(CH2CF,) (pK,(conjugate acid) = 6.3, b = 1 .O(KCI), T = 25 "C) appeared an appropriate choice. In CDC1, solution, 111 exists as an equilibrium 3/1 mixture of two conformers tentatively assigned as IIIa,b;'O line shape analysis of the CH2CH3quartets at 6 3.67 (minor) and 3.46 (major) gives AG*,ooc(major minor) = 14.1 kcal/mol and AGflooc(minor major) = 13.5 kcal/mol as the barriers to rotation about the amidic bond. These values are only slightly lower than those found for a variety of R-substituted N,N-dimethylbenzamides in CDCI, (1 4.5-1 6 kcal/mol)."
-
-
Results and Discussion Our search for a tertiary toluamide that exhibits large amounts of I8Oexchange accompanying its base hydrolysis was guided by earlier work on amine LA from the intermediates TI- produced from base hydrolysis of amidines7q9(eq 2). It is generally believedg H
I
0
f R+NHR,
+
H~O
R L N H R ,
+
NHRzR3
(2)
that TI- produced from an unsymmetrical amidine partitions with the expulsion of the more basic amine. The preference is not absolute, however, since exceptions exist wherein a more sterically demanding, but less basic, amine is the better leaving W e have also shown that amine partitioning from unsymmetrical toluamidines hydrolyzed in base at 100 O C parallels the ordering exchange for the corresponding amide so that the LA of of '*O the amine from To- or TI- is R 2 N H > R N H 2 > NH,.7 W e must point out that basicity arguments alone cannot explain why H N (CH,), (pKa(H2N+(CH,),) = 10.64) departs a t 10-50-fold better from To- or TI- than does H 2 N C H , (pK,(H,N+CH,) = 10.62); here solvation or steric effects could affect the relative LA. Finally, it must be mentioned that the trends suggested for amine departure from TI-could be different from those in neutral or postively charged tetrahedral intermediates. Indeed, Page, Webster, and Ghosezgc have reported that neutral tetrahedral intermediates produced from O H - attack on azetidin-2-ylidenammonium salts preferentially expel the amine containing an electron-withdrawing substituent. (9) (a) Perrin, C . L.; Nufiez, 0.J . Am. Chem. SOC.1987, 109, 522; 1986, 108, 5997 and references therein. (b) Burdick, B. A,; Benkovic, P.A,; Benkovic, S. J. fbid. 1977, 99, 5716. (c) For a discussion of amine basicity influences on LA from neutral tetrahedral intermediates, see: Page, M. 1.; Webster, P. S.;Ghosez, L. J . Chem. SOC.,Perkin Trans. 2 1990, 813.
major IIIa
minor IIIb
Given in Table I are khyd and k,, data for I11 and IV in H 2 0 and D 2 0 ( T = 100 OC, ~1 = I .O (KCI)). In H 2 0 , the rate constants were determined a t two [OH-] in order to determine that each of k,, and khydwas linearly dependent on [base]. For all amides investigated, this was found to be the case in the range of concentrations used. The most striking aspect of the data for 111 is the large amount of exchange (kex/khyd = 33.4 f l.6), which indicates that the intermediate(s) formed must partition back to starting amide a t least 65-70 times faster than proceeding to products. By comparison of the kcx/khydratio for 111 and I or 11: it is apparent that the structural change of incorporating CF, into the amine unit leads to a 2300-3500-fold diminished leaving ability from To- relative to HN(CH,), or pyrrolidine. The data in Table I allow several definitive conclusions to be made. First, that both k,, and k h y d for the amides in Table I and for I and 117 are first-order in [OH-] requires that the transition states leading to exchange and hydrolysis each have one O H incorporated. Second, that tertiary amide I11 exhibits so much exchange reinforces our earlier conclusion^^^^ that stereoelectronic factors (as proposed by Deslongchamps et are unimportant in determining whether a tertiary amide will or will not exchange. In that a n a l y ~ i sthe , ~ reluctance of N,N-dimethylbenzamide2a or N,N-dimethyltoluamide6a to exchange is necessarily attributed to an inability of their respective To- to attain conformational equilibration a t N that would be required to assist in ejecting I80H-. In the case of the hydrolysis of 111, the steric bulk of the amine is expected to be similar to or greater than that in the case of the latter two amides. Thus, if anything, conformational equilibration a t N in To- is expected to be slowcr in the case of 111 than in I or 11 so that less exchange should be observed for the former. That this is not the case strongly suggests conformational mobility a t N either is unimportant or is completely attained for 1-111. In either event, the data would indicate that stereoelectronic effects4 are of minimal importance in explaining the exchange and that LA of the amine dominates. (a) D20Effects with 111 and IV. In the case of I11 if the kinetics are interpreted within the context of the mechanism in eq I , then ( I O ) Lewin, A . H.; Frucht, M . Org. Magn. Reson. 1975, 7, 206. ( 1 1 ) Fong, C. W.; Lincoln, S. F.; Williams, E. H. Aust. J . Chem. 1978, 31, 2615.
Base Hydrolysis of a Tertiary Amide
J . Am. Chem. SOC.,Vol. 113, No. 4, 1991
the rate-limiting step for hydrolysis must be k2, the breakdown of the intermediate. Thus, the anionic tetrahedral intermediate must be produced in a preequilibrium since kex/khydis -33. The D 2 0 results for k,, in I11 then have a strong bearing on the two critical assumptions that are necessary for the use of I8Oexchange to probe reversible formation of intermediate^.'-^ These assumptions require the following: ( I ) the intermediates that lead to exchange are on the hydrolytic pathway and (2) protonic equilibration of the l60and I8O atoms is faster than reversal of T,. The first assumption as discussed by Jenckst2seems eminently reasonable (but as yet unproven) unless one envisions a concerted mechanism leading to exchange, which involves several proton transfers (as in V) occurring in a side reaction at a rate that is U
i‘
‘-0
/H h
V fast relative to the lifetime of To-. A process such as that in V is anticipated to exhibit a large, normal solvent kinetic isotope effect (SKYE).I3 The (kex)H/Dratio for 111 of 0.90 f 0.08 shows no such large solvent isotope effect, which attests to the validity of assumption I , a t least in the hydrolysis of 111. Also if proton transfer via intervening L 2 0 molecules were in some way limiting atoms, that process would be retarded the equilibrium of 160/180 in D 2 0 and k,, should decrease. Since the SKIE is about unity, protonic equilibration of the I6Oand I8Oatoms cannot be substantially slower than breakdown, so the second assumption also appears valid. The experimental observations are that the SKIE is 0.91 f 0.18 0.92 f 0.05 ( H ) , ~and 1.05 f 0.04 (111) for the khyd of three tertiary amides and that the SKIE for k,, ranges from 0.61 f 0.12 to 0.30 f 0.05 (11)7 and 0.90 f 0.05 (111). (These calculations for I 1 I use data at 1 .O N OL- since the isotope effects were only determined at this concentration.) For I and 11, which exhibit low amounts of exchange, the (kex)H/Dvalues differ by more than the sum of their standard deviations but less than twice this sum so that, at the 95% confidence level, we cannot say that they are different. The problem lies in the accuracy with which low amounts of I8Oexchange can be determined,7 but in the case of 111, which shows large amounts of I80exchange, (kex)H/Dis reliably given as 0.90 f 0.05. For I and I1 since exchange is small relative to hydrolysis, the observed values of the rate constants are the following:
-
khyd = klk2/(k-l + k2) k,, = k,k-l/2(k-,
+ k2)
N
kl klk-l/2kz
kex/khyd = k-I /2k2
For 111 where hydrolysis is small relative to exchange, the observed rate constants are the following: khyd
E
klk2/k-l
kex
E
kl/2
kex/khyd = k-l/2k2
Thus, in both limiting cases, it is possible to obtain simple expressions for all of the isotope effects. From the above, the SKIE on k,, for 111 and on khyd for I and 11 are expected (and found) to be similar since each of these is essentially dictated by k , , the attack of OH- on the amide. We analyze the expected S I E on k,, and khydin terms of the anticipated fractionation factorsI3 according to k D / k H = lldTS/lldGS where ndGS is the product of the fractionation factors ( I 2) Jencks, W. P. Catalysis in Chemistry and Enzymology; McGrawHill: New York, 1969; pp 508-517. ( I 3) (a) Schowen, R. L. In Isotope Effects on Enzyme Catalyzed Reactions; Cleland, W. W . ,OLeary, M. H., Northrup, D.B., Eds.; University Park Press: Baltimore, 1977. (b) Schowen, R. L. Prog. Phys. Org. Chem. 1972, 9, 275. (c) Schowen, K . B. J . In Transition States of Biochemical Processes; Gandour, R. D., Schowen, R. L., Eds.; Plenum Press: New York, 1978.
0
1291 0.70
(I_IOH)3 0.78
3
0 ArLNRlR2
OH
(HOH)31 I I I 1-OH 0.7
1.22
(3042
0.91
To-
for the ground state (OH-(H20),) and ndTsare the products of the fractionation factors in the TS for the attack ( k , ) step and breakdown (k2) steps. We assume that the transition states are close to tetrahedral species, with the position of the TS along the reaction being 0.7 for formation and 0.3 for breakdowns7 Also, the primary KIE for a proton in flight between oxygens or oxygen and nitrogen is based on a TS fractionation factor of 0.4 (with values of 0.3-0.5 used as limits).t3a In analyzing the SIE on the k, step for Ill, we follow Gold’s suggestion for OH-:I4 Hydroxide ion has a fractionation factor of 1.22 rather than O S t 3 while the three hydrogens involved in H bonding to OH- have fractionation factors of 0.70. One then assumes three developing H bonds to the amide oxygen, which becomes an 0- similar to OH- in its solvation requirements, and assumes loss of one solvating H 2 0 to allow OH- to attack the carbonyl. Finally, one assumes the fractionation factor for the internal hydrogen of the attacking OHwill be reduced toward that of an OH in a hemiacetal (1 . O 9 , with attendant loosening of its waters of solvation. Given in Figure 1 are the fractionation factors used: Bold-type H’s have the indicated factors, while nonbold H’s have unit fractionation factors. For attack (Figure I ) , the calculated KIE is 0.99, which agrees nicely with the observed KIE on 111 ((kex)H/D= 0.90 f 0.08) and the observed effects on (khyd)HID for I and II.’ The observed (khyd)H/DO f I .05 f 0.04 for III provides information about k2 since the rate-limiting step for hydrolysis is the breakdown of the intermediate to product. Within the mechanistic context of eq 1, the alternatives for breakdown are the following: (a) a concerted path where expulsion of amide ion occurs with simultaneous proton transfer from H20, (b) a stepwise path where a preequilibrium proton transfer from H 2 0 occurs, (b’) the same pathway with rate-limiting proton transfer, (c) a cyclic concerted path involving simultaneous C-N cleavage and a water-mediated proton shift from hydroxyl to N , (d) a process with a preequilibrium intramolecular proton transfer leading to an anionic zwitterion (Tzw-), and (d’) the same path with a rate-limiting proton transfer. These pathways with the associated fractionation factors are given in Figures 2 and 3. Pathways a, b, and b’ (Figure 2) lead to a product set consisting of carboxylic acid, amine, and OH-, while paths c, d, and d’ (Figure 3) lead to carboxylate and amine. For formation of both product sets, those processes that involve protons in flight as part of the rate-limiting step (pathways a, b’, c, and d’) are expected to show large normal isotope effects,13 these being proportional to the number of OL bonds being broken. Only paths b and d are expected to show small isotope effects, since all the associated proton switches occur prior to the ratelimiting C-+NHRlR2 cleavage. For paths b and d with use of the fractionation factors in Figures 2 and 3, the calculated KIE values are 1.47 and 1.86, respectively, and arises not from protons in flight but from reordering of several solvent molecules in the C-N cleavage TS. These calculated SKIE values could be further reduced toward the observed value of 1.05 by slight increases in any of the associated fractionation factors. Although for the analyses presented in Figures 1-3 we have used a fractionation factor for the alkoxy oxygen in the tetrahedral intermediates similar to that of OH- (0.7013),an alternative appropriate choice could be that for CH30- (0.7413). With use of the latter value and the assumed position of the breakdown TS as 0.30, the
-
(14) (15)
Gold, V.; Grist, S. J . Chem. Soc., Perkin Trans. 2 1972, 89. Bone, R.; Wolfenden, R. J . Am. Chem. Soc. 1985, 107,4772.
Slebocka- Tilk et al.
1292 J . Am. Chem. SOC.,Vol. 113, No. 4, 1991 @OH), 0.78
a
f
0 A r t - -NR1R2 Ho
H 0.4
6-H
1.07
(HO& 0.91
OH
(HOHh 0.70
6L
L
Ar+YlR2
"'1'' 7 Hi) I
HO '
I)0.4
-&H
-
I
H
,
1.1
-4-H 1.22
(How2
(How2
0.84
0.70
Tm*OH Figure 2. Possible pathways for breakdown of To- to carboxylic acid and RIR2NH:OH- encounter complex with associated fractionation factors. @OH), 0.78
6 II 08,
0.9 1
Figure 3. Possible pathways for breakdown of
r
H
@OHh 0.70
mOQ3 0.70
To-to amine and carboxylate products with associated fractionation factors.
calculated S K l E for path b is 1.27 and for d is 1.39. The observed SKlE on khyd for 111 is consistent with either of paths b and d but does not allow a distinction to be made between them. Previously, on the basis of energetics calculation^,^ path d was considered as most likely for I and 11 since it was consistent with the H , 0 / D 2 0 SKIE data and required realistic appearing intrinsic barriers for C-N cleavage from TZw-. Breakdown of an anionic zwitterion has also been proposed by Bender and Thomas for the OH- hydrolysis of anilides.I6 A necessary consequence of the two product-forming pathways b and d is that, in the reverse direction, amide formation under basic conditions should proceed by uncatalyzed attack of the amine on carboxylate (d) or its kinetic equivalent, attack on a carboxylic acid by an amine that is hydrogen bonded to OH- in a preassociation complex (16)
'' N y 2 g 0.4
Jencks, W. P. Acc. Chem. Res. 1980, 13, 161.
(b).I6 In the latter case, proton removal from the amine occurs after the C-N bond-forming reaction so that the hydroxide catalysis refers to trapping of TZwand not to concerted proton abstraction while C-N bond formation is taking place. An analogous process has been suggested for ester aminolysis, but in this case the catalysis by OH- was suggested to arise from diffusion-limited trapping of the zwitterion." ln the present case, the latter mechanism also requires that the proton back-transfer required to interconvert Tzw.OHTo- must be faster than diffusional separation of OH- from Tzw and that breakdown of TZw.OH- to product must also be faster than diffusional separation. In the case of secondary amide 1V where the kex/khyd ratio in H,O is 0.49 f 0.03, the intermediates partition between reversal (17) Jencks, W. P. Chem. Reo. 1972, 72, 705.
Base Hydrolysis of a Tertiary Amide
J . Am. Chem. SOC.,Vol. 113, No. 4, 1991 1293
Table 11. Activation Parameters for the Base-Catalyzed Hydrolysis of 1-111, V, and VI"
as'
AH'
=
AG'lch3 o c
(kcdl mol-') (cal K-' mol-I) (kcal mol-') amide -29.5 (0.6) 20.1 f 0.4 p-toluylaziridine (V)b 9.1 (0.2) -29.6 (0.6) 25.6 f 0.4 p-toluylazctidinc (VI)c 14.6 (0.2) -32.9 (1.7) 27.1 f 1.2 Id 14.8 (0.6) 18.2 (0.9) -26.4 (2.5) 28.0 f 1.8 II t IIV 16.4 (0.6) -35.5 (1.5) 29.6 f 1.2 = 1.0 (KCI). *Temperatures used: 5.7, 13.0, 20.5, 27.4, 34.3, 41.5, 48.1 OC. CTemperatures used: 25, 37.1, 49.5, 58.3, 70.6 "C. dTemperatures used: 49.8, 62, 74.4, 100 OC. eTemperatures used: 56, 65, 80, 100 "C. /Temperatures used: 72, 84.5, 100 O C . a
khyd
ki[OH-I(kz k-l + k2
+ k,[OH-l)
+ k3[OH-]
k-lk, [OH-] kex =
2(k-, + k2 + k,[OH-]) and if k2 >> k3[OH-] (as in the case of the presently discussed toluamides), kex/khyd= k-,/2k2. Terms second-order in [OH-] are reported for the hydrolysis of acetanilides,le f ~ r m a n i l i d e s , ~ trifluoroacetaniIides,l8 and acetyl- or benzoyl pyrrole^.^^ This is interpreted in terms of a mechanism (eq 4) wherein a second OH-
--
b
0-
VI1 MG~'= 2.7
kcal/mol
A d = 27.1
kcal/mol
Figure 4. Free energy diagram for base-promoted hydrolysis of 11 (a) and I l l (b) from k,, and khyddata ( T = 100 O C , ~1 = 1.0 (KCI)). AG' = AH' - TAS'; AAG' = -RT In (2kex/khyd).
and product formation with nearly equal propensity. In this case, (kex/khyd)H,Dcompares the SKIE on the two transition states directly, the value being 0.92 f 0.09. This value is consistent with the (kex/khyd)HID value of 0.86 f 0.07 for 111 in which the forward and reverse transition states differ markedly in energy so that IV and 111 apparently hydrolyze by similar mechanisms. (b) Activation Energies for Tertiary Toluamides. Given in Table I 1 are the activation energies for base hydrolysis of 1-111 as well as the aziridine (V) and azetidine (VI) derivatives in aqueous solution ( p = 1.0). It is of note that, for all amides, the entropies of activation are large and negative and a t 100°C contribute between 43 and 55% to the free energy of activation. In the case of I, 11,7 and V,6bwhich show little or no exchange accompanying hydrolysis, the activation parameters refer essentially to k,. This is probably true also for VI, although we have not conducted the pertinent I80-exchange measurements. In the case of 111, the activation parameters pertain to k2, the breakdown of To- via TZwor TZw.OH-. In either limiting case in accordance with the SKIE data for I, 11,7 and 111, the large - a t values are consistent with restriction of water of solvation in the transition states leading to or away from To-.Shown in Figure 4 are two-dimensional reaction coordinate diagrams for 1 and 111 based on the data in Tables I and 11. (c) Unified Approach to Predicting the Mechanism of Base Hydrolysis of Amides. The more complete mechanism for base is an expansion of that given in hydrolysis of amides (eq 3)'e933'8
0
n-
1- kz
TO-
eq 1 . In unbuffered media, steady-state treatment gives the following: (18) (a) Young, J. K.; Pazhanisamy, S.; Schowen, R. L. J . Org. Chem. 1984, 49, 4148 and references therein. (b) Ericksson, S. 0. Acta Chem. Scand. 1968, 22, 892 and references therein. (c) Pollack, R. M.; Dumsha, T. C. J . Am. Ckem. SOC.1973,95,4463. (d) Biechler,S.; Taft, R. W. J . Am. Chem. Soc. 1957, 79, 4927.
removes a proton from a reversibly formed T, to yield a dianion VII, which subsequently expels amide ion, with or without general-acid assistance by solvent. At high [OH-], this trapping of To-effectively halts the reversal and the kinetics become first-order in [OH-] so that formation of To- is the rate-limiting step. N methylation of formanilides3 and acetanilides'8s20tends to decrease the k-,/k2 ratio so that reversibility from To-is diminished, but not eliminated, relative to the corresponding N-H derivative. This type of N-substitution behavior is also seen for T i produced from benzamides and toluamides as determined from the diminished kex/khydratio in passing from secondary to tertiary derivative^.'.^,^,' N-Meth ylacetanilides and N-methyl formanilides can show evidence of second-order terms in [OH-], although this is generally observed only a t high pH since the k3/k-1 ratio is
